The overall objective of this research is to develop, validate, and implement mathematical models for the transmission and within-host dynamics ofbioterrorism agents or naturally occurring infectious diseases. These models will be used to assess the effectiveness and efficacy of various interventions to aid the distribution and allocation of resources in response to such outbreaks. Specific aim 1 is to develop epidemic simulation models for the transmission of infectious diseases in question: a. to develop stochastic epidemic simulation models for a typical American community; b. to use the epidemic simulation models to evaluate the effectiveness of interventions involving surveillance and containment, vaccination, antimicrobials, closing of key institutions, and other control strategies; c. to develop stochastic optimization methods to find the best intervention strategy, constrained by the resources available; d. to adapt the epidemic simulation models for smallpox, pandemic influenza, SARS, and other possible bioterrorism agents or naturally occurring infectious diseases; e. to use the epidemic simulation models to determine the important parameters for infection transmission and to use this information to design field studies and intervention studies; f. to use and develop statistical methods to estimate the important parameters and variables from data. Specific aim 2 is to develop models of the within-host dynamics of pathogens which cause acute infections in vertebrates: a. to construct exploratory models for the interplay between the pathogen and host immune response; b. to refine, to develop further and to test these models of pathogenesis including the use of existing data on lymphocytic choriomeningitis virus (LCMV) and listeria monocytogenes (LM) infections of mice; c. to use the experience from the specific aim 2.b. to extend the models in the specific aim 2.a. to examine the more challenging acute infections of humans including bioterrorism agents or naturally occurring infectious diseases; d. to model development of resistance under selective pressure by antimicrobial and antiviral treatment and prophylaxis by antimicrobials or vaccination; e. to combine the stochastic epidemic simulation models with models for within-host generation of resistance to examine spread of resistance within the host population.